A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.

Pharmacogenet Genomics 2012 Nov;22(11):796-802

Department of Statistics, North Carolina State University, Raleigh, North Carolina 27695-7566, USA.

Objective: Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.

Methods: In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.

Results: Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.

Conclusion: The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.

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November 2012
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